Despite extraordinary advances in drug development and biotechnology, cancer remains a leading cause of death worldwide. The problem often lies not with the drugs, but rather the difficulty in successfully delivering them to the site of a tumour. In healthy tissue, there is a regular structure of blood vessels. These supply oxygen and nutrients to cells, which divide and grow at a steady rate. In cancerous tumours, however, cell division and growth is unregulated. This leads to a chaotic vessel structure and regions of tissue with little or no blood supply. As a result, when drugs are ingested or injected into the blood stream, not all parts of the tumour are treated. With cancerous cells left behind, there is a high risk of recurrence. Adding to this, the pressure inside many tumours is higher than in the blood vessels around them. This inhibits the uptake of drugs meaning only a small fraction is actually delivered. The rest of the drug stays in the blood system until it is absorbed by healthy tissue, often with harmful side effects.
The aim of the research we are carrying out in the Oxford Institute of Biomedical Engineering (IBME) is to explore new methods for delivering anti-cancer drugs that overcome these barriers. There is a formidable series of challenges to address.
First we need to temporarily deactivate the drug to prevent it affecting healthy tissue before it reaches the tumour. Second, to maximize the concentration of the drug in the tumour, we need to localise it after injection. Third, once it has accumulated in the target area, we need to be able to release the drug ‘on demand’. Fourth, the drug must then be distributed uniformly throughout the tumour volume. Finally, it is crucial that we can monitor the treatment from outside the body.
Our team at the IBME has developed a range of new techniques to address these challenges. By creating micro and nanoscale particles, we can precisely package drugs for targeted delivery. To activate the drug after injection, we can exploit a range of different phenomena. These include using materials that are sensitive to the pH change within a tumour or materials that break down when heated. We can also use materials that undergo a phase change, for example from a solid to a liquid, or liquid to a gas.
One of the most versatile means of triggering drug release is ultrasound. Often used in medical imaging, it is completely non-invasive. Unlike light or heat, it can be focused deep within the body to produce highly localized effects. To make particles responsive to ultrasound, we need to fill them with a gas or volatile liquid. When exposed to ultrasound, the gas or liquid expands rapidly, forcing the drug out of the particle. This leaves behind a pulsating gas or vapour bubble, and it is the motion of the bubble that helps drive the drug out of the blood vessels and deep into the surrounding tumour.
Our research shows bubbles can push drugs up to four times deeper into tissue than they would normally diffuse. This is enough to achieve uniform distribution throughout a tumour. Research also shows cancer cells themselves become more permeable when exposed to microbubbles and ultrasound. This increases uptake of the drug and leads to cell death. Lastly, the motion of the microbubbles produces a secondary ultrasound signal that can be detected outside the body. Scanners can track the location and activity of the bubbles, providing real time feedback treatments.
Our aim over the next five years is to translate these developments into clinical use. This includes improving the delivery of drugs whose efficacy is hindered by poor tumour uptake and dangerous side effects. We will also investigate new ways of concentrating drugs at the target site. One method is to use magnetic bubbles that can be dragged to the tumour using an external magnet. Another could ’tag’ particles with molecules causing them to bind only to cancer cells. Once we have cracked the delivery method, we will be able to scale up production of drug loaded particles. There will be a period of pre-clinical testing, before commencing clinical trials in 2020.
Image credit: Valerio Pereno.